Mutual Regulation of Growth Hormone and Bone Morphogenetic Protein System in Steroidogenesis by Rat Granulosa Cells
Mutual Regulation of Growth Hormone and Bone Morphogenetic Protein System in Steroidogenesis by Rat Granulosa Cells
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DOI：
10.1210/en.2011-1646
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发表时间：
2012-01-01
期刊：
影响因子：
4.8
通讯作者：
Makino, Hirofumi
中科院分区：
文献类型：
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作者：
Nakamura, Eri;Otsuka, Fumio;Makino, Hirofumi
生长激素诱导腔前卵泡生长和分化，伴卵母细胞成熟。然而，生长激素对卵巢类固醇生成的影响及其作用机制尚未阐明。本研究通过对卵巢骨形态发生蛋白（BMP）系统的研究，探讨了生长激素对大鼠早期窦卵泡颗粒细胞类固醇生成的影响。我们发现生长激素通过降低芳香化酶表达抑制fsh诱导的雌二醇产生，相反，生长激素通过诱导类固醇急性调节蛋白、侧链切割细胞色素P450和3 β -羟基类固醇脱氢酶增加fsh诱导的孕酮水平。在BMP拮抗剂noggin的存在下，生长激素对颗粒细胞类固醇生成的影响增强。生长激素与卵母细胞共培养不改变生长激素对类固醇生成的调节。由cAMP供体诱导的类固醇生成不受生长激素治疗的影响，生长激素对fsh诱导的类固醇生成的影响不伴随着cAMP合成的变化，这表明生长激素的作用不是由cAMP-蛋白激酶A途径直接介导的。生长激素对FSH诱导的MAPK活化发挥协同作用，调控FSH诱导的类固醇生成。此外，gh诱导的信号转导因子和转录磷酸化激活因子也参与了IGF-I表达的诱导。生长激素增加颗粒细胞中IGF-I、IGF-I受体和FSH受体的表达，抑制IGF-I信号可以恢复生长激素对FSH诱导的孕酮产生的刺激，这表明内源性IGF-I在功能上参与了生长激素对孕酮诱导的作用。BMP通过抑制GH/IGF-I系统的表达来抑制IGF-I增加fsh诱导的雌二醇产生的作用，而GH/IGF-I作用通过下调BMP受体的表达来破坏BMP- sma和Mad相关蛋白1/5/8信号。因此，生长激素通过颗粒细胞内源性IGF-I活性来调节雌激素和孕酮的产生，其中GH-IGF-I相互作用导致BMP的拮抗，包括抑制fsh诱导的孕酮产生。生长激素/IGF-I和BMP信号强度之间的相互平衡可能是调节促性腺激素诱导的生长卵泡中类固醇生成的关键。（内分泌学153:469-480,2012）
GH induces preantral follicle growth and differentiation with oocyte maturation. However, the effects of GH on ovarian steroidogenesis and the mechanisms underlying its effects have yet to be elucidated. In this study, we investigated the actions of GH on steroidogenesis by rat granulosa cells isolated from early antral follicles by focusing on the ovarian bone morphogenetic protein (BMP) system. We found that GH suppressed FSH-induced estradiol production with reduction in aromatase expression and, in contrast, GH increased FSH-induced progesterone level with induction of steroidogenic acute regulatory protein, side chain cleavage cytochrome P450, and 3 beta-hydroxysteroid dehydrogenase. The effects of GH on steroidogenesis by granulosa cells were enhanced in the presence of the BMP antagonist noggin. Coculture of GH with oocytes did not alter GH regulation of steroidogenesis. Steroid production induced by cAMP donors was not affected by GH treatment and the GH effects on FSH-induced steroid production were not accompanied by changes in cAMP synthesis, suggesting that GH actions were not directly mediated by the cAMP-protein kinase A pathway. GH exerted synergistic effects on MAPK activation elicited by FSH, which regulated FSH-induced steroidogenesis. In addition, GH-induced signal transducer and activator of transcription phosphorylation was involved in the induction of IGF-I expression. GH increased IGF-I, IGF-I receptor, and FSH receptor expression in granulosa cells, and inhibition of IGF-I signaling restored GH stimulation of FSH-induced progesterone production, suggesting that endogenous IGF-I is functionally involved in GH effects on progesterone induction. BMP inhibited IGF-I effects that increased FSH-induced estradiol production with suppression of expression of the GH/IGF-I system, whereas GH/IGF-I actions impaired BMP-Sma and Mad related protein 1/5/8 signaling through down-regulation of the expression of BMP receptors. Thus, GH acts to modulate estrogen and progesterone production differentially through endogenous IGF-I activity in granulosa cells, in which GH-IGF-I interaction leads to antagonization of BMP actions including suppression of FSH-induced progesterone production. Mutual balance between GH/IGF-I and BMP signal intensities may be a key for regulating gonadotropin-induced steroidogenesis in growing follicles. (Endocrinology 153: 469-480, 2012)